In 2010, the World Health Organization estimated that 39 million people worldwide face blindness; approximately 10% as a result of age-related macular degeneration (AMD) and diabetic retinopathy (DR). The incidence of DR and AMD is increasing as the population ages and the diabetic epidemic spreads throughout the developing world. Moreover, new diagnosis of both non-proliferative and proliferative DR is associated with an increase in wet (exudative/neovascular) AMD. As recent as 2012, approximately 93 million people suffer from DR; over 70% of which endure vision-threatening complications stemming from an exudative retina. Intravitreal injection of anti-VEGF protein therapeutics is most often used to treat AMD and DR, despite the fact that a significant number of patients are refractory. In addition, there is evidence that early efficacy of anti-VEGF interventions may be lost after long-term (i.e, >2 years) exposure. Mounting evidence supports a role for endogenous VEGF in maintenance of visual function through protection of the choriocapillaris and the neural retina. Together, these data suggest that long-term use of anti-VEGF protein therapeutics may contribute to visual impairment by removing an essential support mechanism for the neural retina.
Paxillin is a phosphotyrosine-containing protein in cells that serves as a docking protein, recruiting signaling molecules to a specific cellular compartment, the focal adhesions, and recruiting specific combinations of signaling molecules into a complex to coordinate downstream signaling. Paxillin-coordinated signaling plays a role in the regulation of cell migration, motility and survival. There is a need for compounds that effectively inhibit paxillin function. Accordingly, the present invention describes compounds according to Formulas (I), (Ia), (II), (III), and (IV), as inhibitors of paxillin, and a companion ocular microemulsion (ME) delivery system.